Switch for transdermal patch

ABSTRACT

A transdermal device such as a patch can include a drug source, a porator, and an energy storage device on-board the patch. The porator operates free of any concurrent connection to any external source of power. A switch can be used to make the selective electrical connection between the porator and the energy storage device. The switch can be arranged to respond to a manual user action after the patch has been adhered to skin, including separation of the porator from a remainder of the patch. Optionally, a series of switches can make electrical connections between the porator and respective individual energy storage devices.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority, under 35 U.S.C.§119(e), of U.S. Provisional Application Ser. No. 60/941,244, filed May31, 2007, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to transdermal devices, and, in particular, to adisposable transdermal device having on-board power for microporatingskin.

BACKGROUND OF THE INVENTION

Transdermal drug delivery and monitoring systems are desirable in manycircumstances in that self-administration by untrained persons isrequired. For example, transdermal drug patches are availablecommercially for curbing nicotine cravings due to smoking, as abirth-control aid, for pain relief, and a wide variety of specificapplications. A principal benefit of transdermal drug delivery ascompared to the historical use of injectable dosage forms is that itprovides the drug directly to the blood stream without the discomfort ofneedles, lancets and other sharp instruments, and without the need fortraining in the use and disposal of such instruments. As compared tooral dosage forms, transdermal delivery can be more effective for someregimens when it is desirable to deliver a drug clear of the hostileenvironment presented by gastrointestinal juices or by first passmetabolism. Further, transdermal devices permit monitoring of bloodcomponents.

A popular form for transdermal drug delivery systems is a patch havingan adhesive layer or perimeter suitable for adhering the patch to skin.A matrix containing a drug or a drug reservoir supplies the drug throughthe skin over a period of time such as several hours or days. Likewise,blood monitoring can be performed through the skin and into the patch.However, skin includes a layer known as the stratum corneum that ischiefly responsible for the barrier properties of skin to preventtransdermal flux of drugs or other molecules into the body and ofanalytes out of the body. The stratum corneum has a thickness of about10 to about 40 microns and is continuously renewed by shedding ofcorneum cells during desquamination and the formation of new corneumcells by a keratinization process. For some drugs, such as opiates, thestratum corneum can impede significant flux, and so it is desirable toovercome this barrier to enable a wider array of topical and transdermaldelivery systems.

It is generally desirable to enhance transdermal drug delivery and bloodmonitoring, and in this regard there are several known methods forincreasing the permeability of skin to drugs. Among these is amethodology known as “microporation” or “poration,” which refers to theformation of a hole or crevice (defined herein as a “micropore”) in abiological membrane, such as skin or mucous membrane, of a patient. Themicropore lessens the barrier properties of the skin to the passage ofdrugs into the patient for a therapeutic treatment, or of biologicalfluids out of the patient for analysis. The micropore can range fromabout 1 to about 1000 microns in diameter and typically extends into theskin sufficiently so as to reduce the barrier properties of the stratumcorneum without adversely affecting the underlying tissues. Typically,multiple micropores are created in a single application of thismethodology. See, for example, U.S. Pat. Nos. 5,885,211 and 7,141,034(the '034 patent) for a description of various thermal and electricalmicroporation techniques and devices.

In order to create micropores, energy is applied to the skin surface. Inthe '034 patent, that energy is provided either by a hand-held externaldevice or from a self-contained unit that combines a transdermaldelivery device with an energy source. The devices proposed by the '034patent are multi-part assemblies, which appear to be cumbersome andawkward to use. It would be preferable to have a light-weight, flexibletransdermal device that is electrically chargeable and fully disposableas compared to the assemblies described in the '034 patent.Alternatively, there are disposable transdermal patches with chemicalreservoirs that can be mixed together to create an exothermal reaction,which might be made suitable for creating a micropore; however, thechemicals required and their associated reactions introduce substantialcomplexities into the manufacture of the transdermal device.

Accordingly, there remains a need for improved methods and devices forthe transdermal delivery of agents such as drugs, and for the monitoringof analytes such as blood components. The present invention concernstransdermal delivery devices of this nature.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, a transdermaldevice is provided with an on-board switch which is connected between anenergy storage device and a porator. The switch makes selectiveelectrical connection to the porator to porate the skin. The switch canbe arranged to respond to a manual user action after the patch has beenadhered to skin.

In another aspect of the invention, any of the transdermal devicesdescribed herein can include a set of chargeable energy storage devicesand associated switches. Each energy storage device can be seriallyconnectable to a porator so as to discharge any stored charge in saidenergy storage device and thereby actuate the porator. A set of switchesconnects the porator to a respective energy storage device in the set ofchargeable energy storage devices. Closure of any given switch in theset of switches makes the connection between the respective energystorage device and the porator.

In accordance with yet another aspect of the present invention, atransdermal patch can comprise the following features. A drug source fortransdermal delivery of a drug through a skin of a user and a dermalcontact layer positioned to maintain the drug source in contact with theskin. A removable carrier supports an electrically-actuatable porator.The porator is removably seated so as to substantially or completelyoverlie the drug source. An on-board energy storage device suitable forstoring an electric potential is supported for selective electricalconnectivity to the porator. Conductive contact terminals extend fromthe energy storage device for connection to an external source of power.The external source of power couples the electric potential and storesit in the energy storage device. As a result of this structure, theporator is actuatable by connection to the on-board energy storagedevice, and will perform its function free of any concurrent connectionto any external source of power.

In a further aspect according to the above arrangement, the removableporator can be configured to have the selective connection of the energystorage device to the porator be established in response to removal ofthe carrier from its seat. Also, the porator can be initially seated soas to overlie at least a portion of the drug source and thereby beproximate to the skin prior to its removal. The porator and its carriercan be separated from the transdermal patch, leaving behind a remainderportion comprising the transdermal contact layer and the drug source.

In accordance with still another aspect of the invention, a transdermalpatch can comprise the following features. A drug source for transdermaldelivery of a drug through a skin of a user, an electrically-actuatableporator, and a dermal contact layer positioned to maintain the drugsource and the porator in contact with the skin, as described above. Theporator can be disposed in a non-removable arrangement relative to thedrug source. An energy storage device suitable for storing an electricpotential is supported for selective electrical connectivity to theporator. Conductive contact terminals extend from the energy storagedevice for connection to an external source of power. The externalsource of power couples the electric potential and stores it in theenergy storage device. As a result of this structure, the porator isactuatable by connection to the on-board energy storage device and willperform its function free of any concurrent connection to any externalsource of power.

In certain embodiments, a mechanical bias is supported in a transdermaldevice of the invention so as to apply a displacement force to a rearsurface of the porator, thereby increasing the likelihood of adequatephysical contact between the porator and the skin. The mechanical biascan assume a stable mechanical state, or the bias can apply a positivepressure that urges the porator into more intimate contact with theskin, or both.

These and other aspects, features and advantages will be apparent from areview of the Drawing Figures and the accompanying discussion of certainembodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1A is a schematic view of an embodiment of a transdermal device inaccordance with the invention in a first arrangement in which a poratoris separable from the transdermal device.

FIG. 1B is a schematic view of the embodiment of FIG. 1A showing analternative arrangement in which a porator is integral with thetransdermal device.

FIG. 2A is a top plan view illustrating a transdermal device accordingto the arrangement of FIG. 1A.

FIG. 2B is a bottom plan view of the transdermal device of FIG. 2A.

FIG. 2C is a cross-section taken along line 2C-2C of FIG. 2A.

FIG. 2D is a detail view of a portion of a manually-actuated switchincluded with the transdermal device of FIG. 2A.

FIG. 2E is a circuit schematic of the switch of FIG. 2D.

FIG. 3A is a perspective view of FIG. 2B, now illustrating the poratorpartially withdrawn from the transdermal device.

FIG. 3B is the top plan view of FIG. 3A, now illustrating the drugsource fully exposed after the porator has been completely separatedtherefrom.

FIG. 3C is a cross-section taken along line 3C-3C of FIG. 3B showing aconfiguration of the transdermal device after removal of the porator andits carrier.

FIG. 3D is a cross-section taken along the line 2C-2C of FIG. 2A showingan optional bias that can be included with the transdermal device in arest position.

FIG. 3E is the cross-section of FIG. 3D, now showing the bias in anactive position in which it applies positive pressure to the porator tourge it into more intimate contact with skin.

FIG. 4A is a top plan view illustrating a transdermal device accordingto the arrangement of FIG. 1A, but comprising multiple energy storagedevices, which can be individually charged and discharged.

FIG. 4B is a cross-section taken along line 4B-4B of FIG. 4A.

FIG. 4C is a detail view of a portion of a series of manually-actuatedswitches included with the transdermal device of FIG. 4A.

FIG. 4D is a circuit schematic of the switch of FIG. 4C.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention provides improvements in transdermal delivery ofagents such as drugs to a user, and monitoring of analytes such as bloodcomponents absorbed transdermally from a user. A transdermal device inaccordance with the invention includes a dermal contact adhesive foraffixation to the skin of a user, as is conventional, and furtherincludes circuitry for microporating the skin. The circuitrycommunicates electrically with an on-board energy storage device, whichcomprises a portion of a single-use, disposable transdermal device. Theenergy storage device stores a charge sufficient to activate one or moreporator elements, and more typically one or more arrays of poratorelements, included in the microporator circuitry in order to disrupt thestratum corneum. Contact terminals extend from the energy storage deviceand provide an electrical connection between the energy storage deviceand an external power source. Preferably a switch provides manualcontrol as to the exact moment(s) that the porator is to be activatedand can be constructed from portions of the device that can be removed,leaving behind a remainder that stays adhered to the skin.

Depending on the construction of the transdermal device, the poratorelement itself can remain a part of the transdermal device afterporation of the skin is achieved, or it can be separated from thetransdermal device. Referring now to FIGS. 1A and 1B, two non-limitingarrangements of a transdermal device are illustrated in the form oftransdermal patches 100, 100′. Both patches include a flexible dermalcontact layer with an adhesive 112 arranged, for example, around theirperimeters for securing to skin of a user. The compliant portions of thedermal contact layer 110 (see FIG. 2C) are intended to conform to theshape of and attach to the skin surface. Optionally, the dermal contactlayer 100 can flex to accommodate any displacement of the layers thatcomprise the patches 100, 100′ without slippage relative to the skin,particularly in embodiments that include a mechanical bias element whichapplies pressure to improve porator-skin contact. The dermal contactlayer may comprise one or more compounds such as, but not limited to, anacrylic, silicone rubber, latex, vinyl, polyurethane, plastic,polyethylene or the like. The dermal contact layer supports the drugsource 120, 120′ included on the patch 100, 100′, respectively, inposition relative to the skin. Suitable adhesives 112 for attachment ofthe dermal contact layer 110 to the skin surface may include any one ofthe large number of existing, medical grade adhesives used in bandages,dressings, and transdermal patches currently being produced. Manymanufacturers, such as 3M, Avery, Specialty Adhesives, and the like,manufacture adhesives that can be useful in this type of application.

Still referring to FIGS. 1A and 1B, the porator 130 is a component, oris the entirety, of the microporator circuitry and is situated so as tohave a front surface in abutting contact with the skin after the patchhas initially been affixed to the user and an opposing rear surface thatcan be supported on a removable or stationary carrier. In thearrangement of FIG. 1A, the porator 130 is separable from the patch 100,as described in more detail below. By separating the porator, the drugsource can occupy a substantial portion of the contact between the skinand the patch 100. In the arrangement of FIG. 1B, the drug source 120′and the porator 130′ are shown interspersed along a surface of the patch100′. In alternative layout arrangements, the porator can surround orpartially surround the drug source 120′. Regardless of its surfacelayout, the porator 130′ is integral to the construction of the patch100′. The porator can comprise an appropriate resistive element such as,e.g., a tungsten, tantalum, or tungsten alloy. The porator can beconstructed as described in aforementioned U.S. Pat. No. 7,141,034. Itis preferred that the surface area of skin porated by the poratorgenerally coincide with the portion of the patch 100, 100′ that deliversthe drug source.

A drug source 120 can take the form of a matrix, a reservoir, orplurality thereof, and is disposed on the patch so that the drug sourceis in abutting contact with the skin after the patch has been affixed tothe user. Examples of transdermal patches that are suitable for use withdrug sources that comprise pain relief compositions, as in preferredembodiments of the invention, include: (1) the matrix-type patch; (2)the reservoir-type patch; (3) the multi-laminate drug-in-adhesive typepatch; (4) the monolithic drug-in-adhesive type patch; and (5) hydrogelpatch. See generally Ghosh, T. K.; Pfister, W. R.; Yum, S. I.Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc. p.249-297, which is hereby incorporated by reference. These patchconstructions are well known in the art and are available commercially.Regardless of the construction selected for a given patch construction,the drug source preferably remains sealed as long as the patch is in itspackaging prior to use. The drug source can be sealed within aliquid-impermeable cover, which can be removed when the patch is readyfor use. One example of a liquid impermeable-cover is the poratorcarrier 132, described below in connection with FIGS. 2 and 3.

As used herein, “reservoir” refers to a designated storage area orchamber within the transdermal device. The reservoir can be designed tocontain a drug for delivery through the skin of a user. Alternatively,the reservoir can be designed to receive a biological fluid sample fromthe skin of the user. A reservoir may further comprise one or moreexcipients typically associated with transdermal delivery devices.Alternatively, a reservoir may further comprise one or more reagentsdesigned to enable the measurement or detection of a selected analyte inan absorbed biological fluid. Where a drug is to be delivered to theuser through the skin, the reservoir serves as a drug source andcomprises a viscous liquid, a gel or a porous polymer comprising aselected drug for release into the skin of the user. Where the reservoiris designed to receive a biological fluid sample from the user forsubsequent analysis, the reservoir serves as a sink to absorb thebiological fluid sample, and comprises a viscous liquid, a gel or aporous polymer adapted for absorption of the biological fluid sample.

As used herein, a “matrix” refers to refers to a portion or the entiretyof the skin-contacting surface of the transdermal device which includesa drug for delivery through an artificial opening in a biologicalmembrane into an organism or which receives a biological fluid sampleextracted from an organism through an artificial opening in a biologicalmembrane, as described above. A matrix could contain, or be treated withany of the excipients or reagents that a reservoir could contain. In onearrangement, the adhesive 112 can overlie a substantial portion or allof the matrix. The drug matrix can be of two types: the drug-in-adhesivesystem and the matrix dispersion system. In the drug-in-adhesive system,the drug is disposed in an adhesive polymer and then the so-medicatedpolymer adhesive is spread, for example, by solvent casting or bymelting the adhesive (in the case of hot-melt adhesives), onto animpervious backing layer. Layers of unmedicated adhesive polymer can beapplied on top of the medicated polymer layer. In the case of the matrixdispersion system, the drug is dispersed homogeneously in a hydrophilicor lipophilic polymer matrix and fixed onto a drug-impermeable backinglayer. The adhesive can be applied as a peripheral adhesive as shown inFIGS. 1A and 1B.

More generally, the matrix or reservoir(s) include a permeant, that is,a first material that permeates another material (skin). The permeantcan be one or more agents such as drugs or for monitoring analytes suchas blood components.

Both patch arrangements will include at least one on-board energystorage device 140, illustrated here as a capacitor. Alternatively, theenergy storage device can be a chemical cell that is energizable so asto store an electric potential suitable for activating the microporatorcircuitry. Contact terminals 150A, 150B are in electrical contact withrespective positive and negative terminals of the storage element 140.For example, one of the contact terminals can be connected to groundpotential while the other is connected to a higher potential, such as 1Volt to 12 Volts, D.C. In this manner, power can be supplied to thecontact terminals from an external source in order to place thetransdermal patch in a “ready-to-microporate” state prior to affixationto the skin and free of any connection to an external or bulky powersource. Thus, the microporating circuitry on board the patch willreceive power from an external power source, yet the external powersource is not required when the porator is actuated.

Optionally, the contact terminals 150A, 150B communicate with conductivetracings of a packaging that surrounds and seals (and possiblyhermetically seals) the patch 100, 100′ until ready for use. The contactterminals 150A, 150B can thus be disposed on a surface of thetransdermal device (as shown in FIG. 2A) so as to make electricalcontact with respective conductive tracings provided on an interior ofthe packaging and thereby transfer electric potential to the energystorage device 140 while the patch remains protected in the packaging.Suitable packaging that can transfer an electric potential to the patch100, 100′ is described in co-pending U.S. Application Ser. No.60/941,157, filed on even date herewith, entitled “Transdermal PatchPackaging,” which is hereby incorporated by reference in its entirety.This arrangement enables power to be supplied through the packaging inorder to place the transdermal patch in a “ready-to-microporate” stateprior to opening the package.

Turning briefly to FIGS. 4A and 4D, the patch 100 (or equivalently patch100′) optionally can be provided with plural energy storage devices 140(e.g., 140A, 140B, 140C, etc.) which can be energized through theterminals 150A, 150B. One of the terminals 150A, 150B can be common toall energy storage devices; in FIG. 4D, terminal 150B is connected toeach of several energy storage devices. The other terminal 150A shouldcomprise plural contacts, each contact being in electrical communicationwith a respective one of the energy storage devices; in FIG. 4D,terminal 150A comprises contacts 152, 154, and 156, and these contactsconnect to the energy storage devices 140A, 140B, 140C, respectively. Asdescribed above, terminals 150A, 150B can be arranged so as to engageconductive tracings provided on an interior of a surrounding packaging.As will be apparent from the discussion below, by dividing terminal 150Ainto plural contacts, the plural contacts can be simultaneouslyconnected to a source of power for simultaneous charging of eachseparate storage device 140A, 140B, 140C, etc. while permitting eachstorage device to be individually and separately discharged when thepatch is affixed to the skin and the poration mechanism actuated. Suchan arrangement permits a staggered series of separate poration events or“pulses,” which can be effective in creating more permeable micropores.

The stored electric potential is releasable from the storage element 140after the patch has been adhesively mounted on the skin so as to createmicropores in the region of the drug source 120, 120′. Release of thestored electric potential is in response to the closing of a switch 160,which as described below includes a stationary contact 166 and a movablecontact 162. Preferably, the switch is manually actuated by a user at adesired moment after the patch has been mounted. The switch can have anyone of a variety of forms, as described below, but a preferredarrangement has the switch constituted by parts that are already to bemoved in order to displace the porator and expose the drug source (inembodiments that have a displaceable porator). Once actuated, the actionof the porator creates micropores of about 1 to about 100 microns acrossand about 10 to about 50 microns deep so as to improve the delivery ofdrug to the user or the absorption of analyte from the user across thestratum corneum.

One embodiment of a transdermal patch 100 having a removable porator 130is illustrated in FIGS. 2A, 2B and 2C. The porator 130 can be seated inregister with a window 102 defined by walls 116 of the dermal contactlayer 110, as shown in FIG. 2B. A removable liner 114 (FIG. 2C) canoverlie the dermal adhesive 112 (as shown), or can comprise a part ofthe packaging for the patch. The dermal contact layer can also include alaminated layer 111 on an opposite side thereof for joining to the drugsource 120.

The porator can comprise a Thin Film Tissue Interface (TFTI) device thatcreates micropores using thermal energy produced by the passage ofelectrical current through resistive elements, as described in U.S. Pat.No. 7,141,034 of Eppstein et al., which is hereby incorporated byreference in its entirety. TFTI devices can create one or moremicropores on a wide range of biological membranes. TFTIs arecharacterized by their ability to rapidly and efficiently create apattern or array of micropores on the surface of a biological membrane.The pattern may be any geometric spacing of micropores with poredensities as high as one pore every 0.2 square mm and covering a totalporated area ranging from a few square millimeters to easily include thesurface area of the entire patch, if desired. TFTI devices are designedto be thin, flexible, conformable structures. Disposable transdermaldevices of the present invention can use TFTI devices without asophisticated controller because each poration element or electrode orother active component (such as a piezo-transducer) in the TFTI can beprovided with an identical drive signal, in parallel to other poratorsin an array, to porate the skin beneath the transdermal device inresponse to a single discharge of energy from the on-board energystorage device. Conveniently, the drive signal can be a current providedin a discharge loop that includes the energy storage device(s) 140.

The porator serves as a heat source to raise the temperature of a smallarea of tissue, typically about 1 to 1000 micron in diameter, to greaterthan about 123° C., preferably greater than about 400° C., which is thenfollowed by a return to ambient skin temperature within a total cycletime of about 1 to about 50 microseconds so as to minimize bothcollateral damage to adjacent tissues and any painful sensation to theuser. The time of energy application is a function of the discharge ratefrom the energy storage device and the length of time the energy isbeing applied to the porator through the closed switch 160. The resultof this application of thermal energy is a vapor-driven removal ofcorneocytes in the stratum corneum. Sufficient energy will thus form amicropore preferably through the stratum corneum and down to the nextlayer of the epidermis, which is the stratum lucidum.

Still referring to FIGS. 2A, 2B and 2C, the porator 130 is supported ona carrier 132 which preferably includes a top panel 134 and a tab 136.The top panel supports the contact terminals 150A, 150B that areelectrically connected to respective terminals of the energy storagedevice 140. The tab 136 is preferably sized for grasping by a user. Thetop panel 134 and tab 136 can be an integral part of the carrier 132.The top panel 132 can be secured to a top surface 104 of the patch 100by a breakable seal 106. The seal can comprise a perforated connectionto the top surface 104 or an adhesive bond. The force required to pullthe tab can be greater than the force required to break seal 106 so thatthe top panel 134 remains attached until a user intends to separate theporator from the patch. Optionally, the tab can include features such aswings 137 which, upon withdrawal of the tab in the direction of arrow A,bear against the seal 106 from below the top panel and assist inbreaking the seal.

The carrier 132 can also support the energy storage device 140, as shownin FIG. 2A. The energy storage device can take the form of a thin filmcapacitor or a fuel cell, both of which are two-terminal storagedevices. Regardless of the form of the energy storage device or which ofthe elements of the transdermal patch 100, 100′ support it, a pair ofconductive leads 141, 142 extend from the energy storage device torespective contact terminals 150A, 150B.

Referring now to FIGS. 2C, 2D and 2E, an embodiment of a switch 160 isdescribed. As illustrated, the tab 136 is withdrawn in the direction ofarrow A which moves a conductive arm 162 into electrical contact withpole 166. When the tab is in a rest position as shown in FIG. 2A, theseal 106, if provided, is unbroken and a leading conductive edge 168 ofthe arm 162 is spaced from pole 166. In this state, the porator is partof an open circuit and not actuated. Meanwhile, the arm 162 is inconductive contact with a circuit node that connects to contact 150A (asshown). As the tab moves in the direction of arrow A, the leading edge168 advances into contact with the pole 166 while the arm 162 remainselectrically connected to the circuit node that includes contact 150A.Continued movement of the tab 136 causes a leading edge of the arm 162to advance to the position shown in FIG. 2D at which the arm 162contacts the pole 166. Such contact completes a series circuit whichincludes the porator 130, as shown schematically in FIG. 2E. The switch160 is closed to actuate the porator and thereby discharge a currentthrough the porator. In one embodiment, the switch closure is inresponse to movement of at least a portion of the carrier, namely, thetab 136. Discharge of substantially all of the stored charge can beinstantaneous in embodiments which utilize a capacitor as the energystorage device, and electrical contact can be made or maintained untilthe tab has been moved beyond the trailing edge of the arm 162. Theporator is intended for single-use, and once it has discharged it can beremoved from the patch, as described below.

Where there are multiple porators forming a porator array in a singlepatch, preferably the porator array is connected in parallel forsimultaneous application of the charge in the energy storage device 140to all of the porators. The power requirement to deliver sufficientenergy to the array to raise the temperature of the skin under the arraycan be determined in view of the number of porator elements and size ofeach porator in the array, their respective resistances, the duration ofenergy application (e.g., about 1 millisecond) and consideration of theextreme current handling capabilities of the porators (e.g., 40Amperes). Based on these parameters, an energy storage device 140 can beselected with sufficient capacity to drive the porator array to achieveits intended purpose.

Once the porator has been used to disrupt the stratum corneum, theporator can be removed from a remainder of the patch 100.

Referring now to FIGS. 4B, 4C, and 4D, the switch 160 in this embodimentcomprises plural conductive arms 162A, 162B, 162C that cooperate withthe stationary pole 166 to complete respective series circuits thatprovide energy to the porator 130. As illustrated, the tab 136 iswithdrawn in the direction of arrow A which moves the series ofconductive arms 162A, 162B and 162C into serial electrical contact withstationary pole 166. When the tab is in its initial rest position, asshown in FIG. 4B, the seal 106, if provided, is unbroken and the firstconductive arm 162A in the series is spaced from the stationary pole166. In this position, the porator is part of an open circuit and hasnot yet been actuated. Meanwhile, the arm 162A is in conductive contactwith a circuit node that connects to contact 152 (as shown). Likewise,in this rest position the conductive arms 162B and 162C are spaced fromthe pole 166 and are in conductive contact with a circuit node thatincludes contacts 154, 156, respectively. As the tab moves in thedirection of arrow A, the leading edge 168 (see FIG. 4C) advances intocontact with the pole 166 while the arm 162 remains electricallyconnected to the circuit node that includes contact 150A. Continuedmovement of the tab 136 causes the leading edge 168 to advance to theposition shown in FIG. 4C at which the arm 162A contacts the pole 166.This contact completes a series circuit which includes the porator 130and the energy storage device 140A, as shown schematically in FIG. 4D.The switch including arm 162A is closed to actuate the porator 130 usingthe energy in energy storage device 140A and thereby discharge a firstcurrent through the porator 130 by movement of at least a portion of thecarrier, namely, the tab 136. Discharge continues until the tab has beenmoved beyond the trailing edge of the arm 162A, and can be expected tolast on the order of about 1-millisecond.

The length of time that the switch remains closed and the porator canreceive energy varies with the length of the arm 162 along the tab 136of the carrier, and the pull speed by the user in the direction of arrowA. The time of energy application is a function of the discharge ratefrom the energy storage device and the length of time the energy isbeing applied to the porator by a closed switch 160, but generally canbe instantaneous if the energy storage device is a capacitor. In thearrangement of FIGS. 4A-4D, additional porator actuations can beachieved without movement of the transdermal device 100, 100′ relativeto the skin, without the use of an external power source, and withoutthe need for a logic circuit or processor to control the timing ofenergy delivery. Rather, the arrangement shown in FIGS. 4A-4D providesadditional conductive arms 162B, 162C, which are each electricallyconnectable to the porator 130 so as to close respective circuits andapply energy from separate energy storage devices 140B, 140C,respectively. While three conductive arms and three associated energystorage devices are illustrated, fewer or additional conductive arms andassociated energy storage devices can be provided, as desired.

With further reference to FIGS. 4B and 4C, as the tab 136 continues tomove in the direction of arrow A, the conductive arms 162B and 162Cserially engage the stationary pole 166, closing respectively insequence additional circuits, and thereby sequentially applying energyfrom energy storage devices to the porator 130. Each respective circuitcloses when and while the conductive arms 162A, 162B, 162C are incontact with the stationary pole 166.

FIG. 4D illustrates schematically the conductive arm 162A closing afirst energy delivery circuit that supplies energy to the porator 130for discharge of heat into the skin. The circuit is closed because theconductive arm 162A is in contact with stationary pole 166, which is theposition illustrated in FIG. 4C. Meanwhile, conductive arms 162B and162C remain spaced away from the stationary pole, as illustratedschematically as open circuits in FIG. 4D. With continued movement ofthe tab 136 in the direction of arrow A, the circuit including energystorage device 140A opens and shortly thereafter the circuit includingenergy storage device 140B closes. Each closure of the switch 160results in an actuation of the porator 130 and a release of thermalenergy into the skin. These multiple deployments of energy can beeffective in disrupting or reducing the barrier imposed by the stratumcorneum with lower amounts of energy being applied with each circuitclosure than if only a single energy deployment were used. As a result,the user can experience reduced discomfort or sensation from theporation of skin using a transdermal device configured as illustrated inFIGS. 4A-4D.

The timing between the opening of one circuit and the closing of thenext is partially a function of the spacing between the conductive arms162, and also a function of the rate that the user pulls the tab 136. Ofinterest, however, is that a staggered, time-release of energy can beachieved mechanically, without the use of an integrated circuit.Further, such an energy release is in response to a simple manualmovement, such as the pulling of the tab 136. As a consequence of thisunique solution, a fully disposable transdermal device can bemanufactured which is simple for a user to use.

In the embodiments illustrated in FIGS. 1A, 2C, and 4B, removal of theporator after actuation provides unobstructed contact between the drugsource 120 and the skin of the user through the window 102. Because ofthe micropore disruption of the stratum coreum, the patch canbeneficially include a smaller quantity of drug than conventionalpatches because drug flux into the skin is enhanced. Additionally, or inthe alternative, the creation of micropores beneficially ensures thatsubstantially all of a drug transfers from the patch to the user,leaving little or no drug residue in the patch, which is particularlydesirable for patches containing certain controlled substances.

Referring now to FIG. 3A, the carrier 132 of the illustrated embodimentis shown partially separated from the patch. In FIG. 3A, the tab 136 hasalready been fully extended to close the circuit and actuate the porator130 and the top panel 134 has already been pulled in the direction ofarrow A and has been partially pulled in the direction of arrow B (seealso FIG. 2C). As a result, the carrier 132 and the porator 130 arepartially withdrawn from the window 102 to thereby permit the drugsource 120 to contact skin through the window 102. The patch can bemounted to the user's skin, for example, using the dermal adhesive 112that surrounds the window 102, and in other arrangements such as thosein which a matrix is used as the drug source 120, the drug or otherpermeant can permeate the skin through the dermal contact layer 110(FIG. 2C) and adhesive 112 without requiring a window. Continued pullingof the tab 136 fully withdraws the porator 130, leaving behind thatportion of the transdermal device shown in FIG. 3B. The patch can remainon the user's skin for a period of time ranging from minutes to days,depending on the purpose and instructions for any particular patch.After removal of the porator 130 and carrier 132, the portion of thetransdermal device remaining on the skin can have a configuration asshown in the cross-section of FIG. 3C.

FIGS. 3D and 3E illustrate a passive bias mechanism that can be providedon the transdermal device to better ensure positive contact between theporator 130 and the user's skin. In FIG. 3D, the transdermal device 300is a modification of the device of FIG. 2A so as to include a mechanicalbias element 350 that can impart a bias in the direction of the skinonce the device is mounted onto the skin. In FIG. 3D, the mechanicaldevice 350 is in a rest position 350A, and the adhesive 112 is inadhering contact with the user's skin. FIG. 3D exaggerates the distancesto illustrate the benefit of the bias mechanism 350. In particular,after mounting the transdermal device 300 to the skin, a portion or allof the porator 130 may not make adequate or optimal physical contactwith the skin, and this is undesirable because the porator will not beas effective in porating the skin. In FIG. 3E, the mechanical biaselement is shown as it moves toward an activated position 350B, such ascan be the result of a user pressing upon the transdermal device 300after mounting to skin and before activating the porator circuit (e.g.,by pulling the tab 136). In the activated position, the bias mechanism350 flexes into a stable configuration in which it urges the porator 130into contact with the skin (as shown by the motion arrows) and maintainssuch contact. Meanwhile, the material of the dermal contact layer 110flexes so as to accommodate the force applied by the mechanical biaselement 350 while the adhesive 112 remains firmly in adhesive contactwith the skin. In this embodiment, once in the activated position (notshown), the porator 130 can make more adequate physical contact with theskin across the entire surface of the porator 130. The mechanical biaselement can comprise a bias such as made from metal or plastic. The biasshould have a rigidity that is sufficient to maintain its activatedposition 350B as a stable state after being depressed by the user.Because the bias is a passive mechanism, it can be implemented in asimple manner as part of a disposable transdermal device.

Referring again to FIGS. 1B and 2C and as noted above, a patch 100′ canbe configured to have a porator 130′ which is integral to the patchitself. In this arrangement, the patch 100′ can have a window 102 fordelivering a stored energy to the porator 130′ and a drug via a drugsource 120′, or for absorbing and monitoring an analyte as describedabove. Alternatively, the drug in the drug source 120 can be containedin a matrix and can permeate the skin through the dermal contact layer110 and adhesive 112 without requiring a separate window 102. In thepatch 100′, the electrically-actuatable porator 130′ can surround,partially surround, or be interspersed with the drug source 120′, but inthis embodiment the porator is integrated into the patch so that it isnot removable. The porator 130′ can be located on or within thesubstrate that contains the drug source 120′. Thus, the substrate can bea non-conductive material that supports conductive traces that contactat crosspoints to define an array of simultaneously activatedmicroporators. The traces can comprise fibers that are part of a weavesupported by the substrate, or a deposited conductive material, or apreformed wire conductor, or a machined conductive material. Optionally,ends of the microporator(s) can be free to move as the poratorwires/fibers/elements increase in length with the rapid increase intemperature. Optionally, the microporator(s) can self-destruct duringuse to prevent reuse, such as by being provided with a current beyondthe wire's capacity, or by being mounted so that the porator structuremechanically fails during thermal expansion of the material of the wire(e.g. such as where the wires are rigidly mounted and break underexpansion stress, or are mounted to a tearable substrate that yields tothe expansion stress).

Just as described above, the embodiment of FIG. 1B can includeconductive contacts 150A, 150B that extend from the energy storagedevice 140 for connection to an external source of power. The externalsource of power couples the electric potential and stores it in theenergy storage device. A switch 160 provides manual control over thetiming of when the energy storage device discharges its charge. Theswitch 160 can comprise the arrangement substantially as described abovein connection with FIG. 2A-2E or 4A-4D, except that the porator 130′ isnot removable in this embodiment, or can comprise a different switcharrangement. The switch that is used is part of the microporator circuitand enables that circuit to be completed (i.e., to enable a closed loopto be formed which applies the terminals of the energy storage device140 to the porator's terminals). The switch can comprise a depressiblearm on one portion of the patch that contacts an underlying, stationarypole mounted on another part of the patch, or a peelable element thatplaces two circuit points into conductive contact with each other (orpeels away an insulative spacer to permit other elements to move intoconductive contact with one another, or can be a switch that responds tothe environment (e.g., oxygen or light) by changing its state so as topermit conduction suitable to energize the porator.

The porator 130, 130′ transforms the skin into a high efficiencytransport state by disrupting the stratum corneum, and as such atransdermal device including a porator, an on-board energy storagedevice and contact terminals to pre-charge the energy storage device fordisposable use can be used in the delivery of a wide variety of drugsand agents, including those having molecular weights in the range ofabout 300 to about 40,000 daltons.

The terms “agent” and “drug” are used interchangeably herein and areintended to have their broadest interpretation as any therapeuticallyactive substance which is delivered to a living organism to produce adesired, usually beneficial, effect. In general, this includestherapeutic agents in all of the major therapeutic areas including, butnot limited to, anti-infectives such as antibiotics and anti-viralagents, analgesics and analgesic combinations, anesthetics, anxiolytics,anorexics, anti-arthritics, anti-asthmatic agents, anti-convulsants,anti-depressants, anti-diabetic agents, anti-diarrheals,anti-histamines, anti-inflammatory agents, anti-migraine preparations,anti-motion sickness preparations, anti-nauseants, anti-neoplastics,anti-parkinsonism drugs, anti-pruritics, anti-psychotics, anti-pyretics,anti-spasmodics including gastrointestinal and urinary anti-spasmodics,anti-cholinergics, sympathomimetrics, xanthine derivatives,cardiovascular preparations including calcium channel blockers,beta-blockers, anti-arrythmics, anti-hypertensives, diuretics,vasodilators including general, coronary, peripheral and cerebralvasodilators, central nervous system stimulants, cough and coldpreparations, decongestants, diagnostics, hormones, hypnotics,immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetrics, proteins, peptides, polypeptides, antibodies,antibody fragments, and other macromolecules, psychostimulants,sedatives and tranquilizers.

The therapeutic agent can be an opioid agonist, a non-opioid analgesic,a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-IIinhibitor, a 5-lipoxygenase inhibitor, an anti-emetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker,an anti-cancer agent, an agent for treating or preventing UI, an agentfor treating or preventing anxiety, an agent for treating or preventinga memory disorder, an agent for treating or preventing obesity, an agentfor treating or preventing constipation, an agent for treating orpreventing cough, an agent for treating or preventing diarrhea, an agentfor treating or preventing high blood pressure, an agent for treating orpreventing epilepsy, an agent for treating or preventinganorexia/cachexia, an agent for treating or preventing drug abuse, anagent for treating or preventing an ulcer, an agent for treating orpreventing IBD, an agent for treating or preventing IBS, an agent fortreating addictive disorder, an agent for treating Parkinson's diseaseand parkinsonism, an agent for treating a stroke, an agent for treatinga seizure, an agent for treating a pruritic condition, an agent fortreating psychosis, an agent for treating Huntington's chorea, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for inhibiting vomiting, an agent fortreating dyskinesia, an agent for treating depression, or any mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable derivatives thereof, or anymixture thereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable derivativesthereof, or any mixture thereof.

Examples of useful non-opioid analgesics include, but are not limitedto, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,a pharmaceutically acceptable derivative thereof, or any mixturethereof. Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);alkanones, including nabumetone; a pharmaceutically acceptablederivative thereof; or any mixture thereof. For a more detaileddescription of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996); andGlen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19^(th) ed. 1995), which are hereby incorporated byreference in their entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, celecoxib,DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone,nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367,SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, apharmaceutically acceptable derivative thereof, or any mixture thereof.

In the foregoing description, certain features have been described inrelation to certain embodiments of the invention, but these samefeatures are to be understood as being useable in other arrangements andembodiments. Accordingly, the invention is defined by the recitations inthe claims appended hereto and equivalents thereof, and is not limitedto particular details of any of the foregoing embodiments that ratherare provided to facilitate an understanding of the invention and tosatisfy certain statutory requirements.

1. A transdermal patch having an on-board energy storage device forcoupling to an external power source in order to store a charge in theenergy storage device, comprising: a dermal contact layer having anadhesive suitable for securing the dermal contact layer to a skin of auser; a drug source supported by the dermal contact layer fortransdermal delivery of a drug through the skin of the user; anelectrically-actuatable porator disposed so as to substantially orcompletely overlie the drug source; a removable carrier, wherein theporator is supported by the carrier and is removable therewith, theporator being removable by a pulling movement from a rest position inwhich the porator substantially or completely overlies the drug sourceto a second position; the chargeable energy storage device beingselectively electrically connectable to the porator so as to dischargethe stored charge and thereby actuate the porator; and a switchconnected between the energy storage device and the porator for makingthe selective electrical connection to the porator, the switchcomprising a stationary pole and an arm mounted for movement by the userrelative to the pole.
 2. The transdermal patch of claim 1, furthercomprising conductive contact terminals extending from the energystorage device, the contact terminals being connectable to the externalpower source so as to couple an electric potential from the externalpower source and store the charge in the energy storage device.
 3. Thetransdermal patch of claim 1, wherein the arm is mounted on the carrierand wherein the selective connection of the energy storage device to theporator is made in response to movement of at least a portion of thecarrier.
 4. The transdermal patch of claim 1, wherein the carrier isseverally affixed to the transdermal patch so as to be severabletherefrom.
 5. The transdermal patch of claim 1, further comprising atleast one electrically-insulative layer.
 6. The transdermal patch ofclaim 5, wherein the energy storage device is supported on the at leastone electrically insulative layer.
 7. The transdermal patch of claim 1,wherein the energy storage device is supported on either the drug sourceor the dermal contact layer.
 8. The transdermal patch of claim 1,wherein the porator comprises at least one pair of spaced electrodessupported for contact with the skin of the user.
 9. The transdermalpatch of claim 1, wherein the energy storage device comprises acapacitor.
 10. The transdermal patch of claim 1, wherein the drug sourcecomprises a matrix or at least one drug reservoir.
 11. A transdermalpatch having a set of on-board energy storage devices for coupling to anexternal power source in order to store a charge in each of the energystorage devices, comprising: a dermal contact layer having an adhesivesuitable for securing the dermal contact layer to a skin of a user; adrug source supported by the dermal contact layer for transdermaldelivery of a drug through the skin of the user; anelectrically-actuatable porator disposed so as to substantially orcompletely overlie the drug source; a pullingly moveable carriersupporting the porator; each energy storage device being serially,electrically connectable to the porator with movement of the carrier soas to discharge in serial manner first the stored charge in one of saidenergy storage devices in the set and then another of said energystorage devices in the set and thereby actuate the porator multipletimes with continued movement of the carrier; and a set of switches,each switch being connected between the porator and a respective energystorage device in the set of chargeable energy storage devices, wherebyclosure of any given switch in the set of switches makes the connectionbetween the respective energy storage device and the porator.
 12. Thetransdermal patch of claim 11, further comprising conductive contactterminals extending from each energy storage device in the set ofchargeable energy storage devices, the contact terminals beingconnectable to the external power source so as to couple an electricpotential from the external power source and store the charge in all ofthe energy storage devices.
 13. The transdermal patch of claim 11,further comprising a removable carrier, wherein the porator is supportedby the carrier and is removable therewith, the porator being removablefrom a rest position in which the porator substantially or completelyoverlies the drug source to a separated position in which the porator isremote from the drug source.
 14. The transdermal patch of claim 13,wherein each switch comprises a stationary pole and a moveable arm,wherein all of the moveable arms are mounted on the carrier and whereinthe selective connection of the porator to each energy storage device inthe set of chargeable energy storage devices is made in response tomovement of at least a portion of the carrier so as to serially connectto the porator one energy storage device in the set of chargeablestorage devices after another.
 15. The transdermal patch of claim 13,wherein the carrier is severally affixed to the transdermal patch so asto be severable therefrom.
 16. The transdermal patch of claim 11,further comprising at least one electrically-insulative layer.
 17. Thetransdermal patch of claim 16, wherein the set of chargeable energystorage devices is supported on the at least one electrically insulativelayer.
 18. The transdermal patch of claim 11, wherein the set ofchargeable energy storage devices is supported on either the drug sourceor the dermal contact layer.
 19. The transdermal patch of claim 11,wherein the porator comprises at least one pair of spaced electrodessupported for contact with the skin of the user.
 20. The transdermalpatch of claim 11, wherein the set of chargeable energy storage devicescomprise respective capacitors.
 21. The transdermal patch of claim 11,wherein the drug source comprises a matrix or at least one drugreservoir.
 22. A transdermal patch having an on-board energy storagedevice for coupling to an external power source in order to store acharge in the energy storage device, comprising: a dermal contact layerhaving an adhesive suitable for securing the dermal contact layer to askin of a user; a drug source supported by the dermal contact layer fortransdermal delivery of a drug through the skin of the user; anelectrically-actuatable porator disposed so as to substantially orcompletely overlie the drug source; wherein the chargeable energystorage device being selectively electrically connectable to the poratorso as to discharge the stored charge and thereby actuate the porator; aswitch connected between the energy storage device and the porator formaking the selective electrical connection to the porator, the switchcomprising a stationary pole and an arm mounted for movement by the userrelative to the pole; and an elongate flexible carrier configured to bemovable relative to the drug source and the stationary pole, wherein thearm is supported by the elongate flexible carrier and movable therewithso that movement of the elongate flexible carrier relative to the drugsource and the stationary pole causes the arm to electrically contactthe stationary pole to energize the electrically-actuatable porator. 23.The transdermal patch of claim 1, wherein the carrier is pullinglymoveable to discharge the stored charge free of any concurrentconnection to the external power source.
 24. The transdermal patch ofclaim 11, wherein the carrier is pullable to discharge in serial mannerthe stored charge in each said energy storage device free of anyconcurrent connection to the external power source.